IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice

• Published in: The Journal of immunology (1950) 2007-12, Vol.179 (12), p.8274-8279
• Main Authors: Smith, Emily, Zarbock, Alexander, Stark, Matthew A, Burcin, Tracy L, Bruce, Anthony C, Foley, Patricia, Ley, Klaus
• Format: Article
• Language: English
• Subjects: Animals; CD18 Antigens - genetics; Homeostasis - immunology; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - physiology; Interleukin-17 - blood; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukin-23 - genetics; Interleukin-23 - physiology; Mice; Mice, Mutant Strains; Neutropenia - genetics; Neutrophils - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.179.12.8274

IL-23 is secreted by macrophages and dendritic cells in response to microbial products and inflammatory cytokines. IL-23 is a heterodimer composed of the unique IL-23p19 subunit linked to the common p40 subunit that it shares with IL-12. IL-23 is implicated in autoimmune diseases, where it supports the expansion of IL-17A-producing CD4+ Th17 cells. IL-23 also regulates granulopoiesis in a neutrostat regulatory feedback loop through IL-17A-producing neutrophil regulatory (Tn) cells, most of which express gammadelta TCR. This homeostatic system is disrupted in mice lacking adhesion molecules like beta2-integrins (Itgb2-/-) which have defective neutrophil trafficking and neutrophilia. To test the role of IL-23 in the homeostatic regulation of circulating neutrophil numbers, we measured blood neutrophil numbers in p40-deficient (IL12b-/-) mice and found them reduced compared with wild-type mice. IL12b-/-Itgb2-/- mice, lacking beta2-integrins, IL-12, and IL-23 showed significantly blunted neutrophilia compared with Itgb2-/- mice. Treatment of both IL12b-/- and IL12b-/-Itgb2-/- mice with IL-23, but not IL-12, restored circulating neutrophil counts. Serum levels of IL-17A were readily detectable in Itgb2-/- mice, but not in IL12b-/-Itgb2-/- mice, suggesting that IL-17A production is reduced when IL-23 is absent. Similarly, tissue mRNA expression of IL-17A was reduced in IL12b-/-Itgb2-/-mice compared with Itgb2-/- controls. The total number of CD3+ IL-17A-producing Tn cells were significantly reduced in the spleen and lamina propria of IL12b-/-Itgb2-/- mice, with the largest reduction found in gammadelta+ T cells. Our results suggest a prominent role of IL-23 in the regulation of granulopoiesis and the prevalence of IL-17A-producing Tn cells.